Cross-talk between energy and redox metabolism in astrocyte-neuron functional cooperation

Almeida A, Jimenez-Blasco D, Bolaños JP. Essays Biochem. 2023 Mar 3;67(1):17-26. doi: 10.1042/EBC20220075. PMID: 36805653

Abstract: Astrocytes show unique anatomical, morphological, and metabolic features to take up substrates from the blood and metabolize them for local delivery to active synapses to sustain neuron function. In the present review, we specifically focus on key molecular aspects of energy and redox metabolism that facilitate this astrocyte-neuronal coupling in a controlled manner. Basal glycolysis is co-ordinated by the anaphase-promoting complex/cyclosome (APC/C)-Cdh1, a ubiquitin ligase that targets the proglycolytic enzyme 6-phosphofructokinase-2,6-bisphosphastate-3 (PFKFB3) for degradation. APC/C-Cdh1 activity is more robust in neurons than in astrocytes, which determine that PFKFB3 abundance and glycolytic rate are weaker in neurons. The low PFKFB3 activity in neurons facilitates glucose-6-phosphate oxidation via the pentose-phosphate pathway, which promotes antioxidant protection. Conversely, the high PFKFB3 activity in astrocytes allows the production and release of glycolytic lactate, which is taken up by neurons that use it as an oxidizable substrate. Importantly, the mitochondrial respiratory chain is tighter assembled in neurons than in astrocytes, thus the bioenergetic efficiency of mitochondria is higher in neurons. Because of this, the production of reactive oxygen species (mROS) by mitochondrial complex I is very low in neurons and very high in astrocytes. Such a naturally occurring high abundance of mROS in astrocytes physiologically determines a specific transcriptional fingerprint that contributes to sustaining cognitive performance. We conclude that the energy and redoxmetabolism of astrocytes must complementarily match that of neurons to regulate brain function and animal welfare.

Funding: This work was supported by the Agencia Estatal de Investigacion [grant numbers ´ PID2019-105699RB-I00/AEI/10.13039/501100011033, PDC2021-121013-I00, RED2018-102576-T (to J.P.B.)]; Plan Nacional de Drogas [grant number 2020I028 (to J.P.B.)]; Instituto de Salud Carlos III [grant numbers PI21/00727, RD21/0006/0005
cofunded by the European Union (to A.A.)]; and Junta de Castilla y Leon [grant number CS/151P20 cofunded by P.O. FEDER (to ´ A.A.)]; Apoyo Regional a la Competitividad Empresarial, [grant number ICE 04/18/LE/0017 (to J.P.B.)]; and Escalera de Excelencia [grant number CLU-2017-03 (to J.P.B. and A.A.)]. D.J.B. is a recipient of a Juan de la Cierva-Incorporacion contract [grant number ´ IJC2020-044230-I].